PROJECT SUMMARY Cognitive impairment, and specifically Alzheimer?s Disease, is a known sequela of mechanical ventilation and critical illness in older individuals. Although the prevalence of cognitive impairment after critical illness is expected to increase dramatically as our population ages, very little is understood about the specific mechanisms that underlie this finding and there is a significant need for therapies that ameliorate the public health impact of this condition. Prior research to understand the association between mechanical ventilation and cognitive impairment has been confounded by the underlying indication for mechanical ventilation, such as sepsis, surgery, or acute brain injury, all of which could independently contribute to cognitive impairment. To overcome this limitation, we developed a novel model of short-term mechanical ventilation in wild-type and double transgenic Alzheimer?s Disease-model mice to study the isolated consequences of mechanical ventilation in older individuals. Our preliminary data suggest that even short-term mechanical ventilation accelerates the neuropathology of Alzheimer?s Disease by increasing cerebral amyloid-? accumulation, however the exact mechanism by which this occurs remains unknown. We obtained additional data that show cognition-relevant neuropathological changes with elevated right atrial pressure, and now propose to examine whether the increase in right atrial pressure due to positive pressure mechanical ventilation impairs glymphatic clearance, increases blood-brain barrier leakiness, and increases cerebral amyloid-? accumulation -- thus contributing to the pathogenesis of Alzheimer?s Disease. Dr. Lahiri, the PI of this study, is a critical care neurologist and an early-career physician-scientist who developed the novel disease model and generated preliminary data presented in this proposal. Dr. Lahiri? s previous research has focused on short- and long-term clinical effects of mechanical ventilation in acute brain injury, and he is now transitioning his focus to aging-related research. The GEMSSTAR award and associated institutional commitments would provide Dr. Lahiri with the time, resources, and training to launch a successful career in aging-research that focuses on the cognitive effects of critical illness in older individuals.